1. Field of the Invention
The present invention relates to an .alpha.-methylenecyclopentanone derivative and a process for producing the same. The derivative is useful as an intermediate for the synthesis of pharmaceuticals and insecticides, especially prostaglandins.
2. DESCRIPTION OF THE PRIOR ART
.alpha.-methylenecyclopentanone derivatives are now being watched with keen interest because of their usefulness as an intermediate for pharmaceuticals and insecticides. It is especially useful as an intermediate for the synthesis of prostaglandins with high physiological activities.
One of the known processes for the synthesis of prostaglandin represented by the formula (P) is by the conjugate addition reaction. (G. Stark et al., J. Am. Chem. Soc. 97, 4745, 6260 (1975)) ##STR3##
The above-mentioned process is advantageous in that the yield of prostaglandin F.sub.2.alpha. (P) from the compound [IVa] is high and that it is possible to change the .alpha.-chain as desired by selecting an adequate reagent for conjugate addition.
Unfortunately, the known reagent for conjugate addition does not contain a substituent such as COOR.sup.7, CN, and OOCR.sup.8 (where R.sup.7 and R.sup.8 denote alkyl groups having 1 to 6 carbon atoms) which readily reacts with an organometallic reagent. Therefore, such a substitutent had to be formed by conversion. For example, in the synthesis of the above-mentioned prostaglandin F.sub.2.alpha. (P), the CH(CH.sub.3)OC.sub.2 H.sub.5 group is eliminated to form an alcohol which is subsequently oxidized with a chromium-based oxidizing agent (which is toxic) into a carboxylic acid. Such an indirect process poses problems associated with safety and simplicity required for industrial production.
The present inventors proposed in Japanese Patent Application No. 184487/1990 a process for producing prostaglandins advantageously on an industrial scale which have the substituent incapable of direct introduction by the conventional process as mentioned above, using a reagent for conjugate addition which permits the direct introduction of such a substituent. This process comprises performing conjugate addition reaction on an .alpha.-methylenecyclopentanone derivative represented by the formula [IVb] below and an organozinc reagent represented by the formula [V] below in the presence of cuprous cyanide and trialkylsilyl chloride, followed by optional hydrolysis. The reaction product is a prostaglandin precursor having COOR.sup.7, CN, or OOCR.sup.8 as the substituent of the .alpha.-chain. ##STR4## (TBS=SiMe.sub.2.sup.t Bu, Me denoting a methyl group and .sup.t Bu denoting a butyl group) EQU Zn(CH.sub.2).sub.l W.sub.m (CH.sub.2).sub.n Z.sup.1 [V]
(where W denotes a group selected from CH.sub.2 CH.sub.2, CH.dbd.CH, and C.tbd.C; l denotes an integer of 1 to 7; m and n each denote an integer of 0 to 5; Z.sup.1 denotes COOR.sup.7, ##STR5## hydrogen atom, chlorine atom, or a substituted or unsubstituted aromatic group; R.sup.7 and R.sup.8 each denote an alkyl group having 1 to 6 carbon atoms; and Zn denotes zinc.)
The above-mentioned G. Stark's process is disadvantageous in that the yield of the compound [IVa] is low, the reagent used for synthesis is expensive, and the compound [IVa] is usually of racemic modification but is not an optically active substance. (ibid.; D. R. Morton et al., J. Org. Chem., 43, 2102 (1978); and A. B. Kodivsky et al., J. Org. Chem., 49, 2301 (1984)).
Thus, the present inventors proposed in Japanese Patent Laid-Open No. 128/1990 (U.S. Ser. No. 207,549, EP 88.305442.1, Hungary 3090/88) a new process for producing prostaglandin intermediates [IVa] and [IVb] in high yields on an industrial scale. This process comprises performing conjugate addition reaction on an .alpha.-aminomethylcyclopentenone derivative represented by the formula (II) below and an organometallic reagent. Therefore, this process permits an optically active substance to be produced easily in high yields from an inexpensive raw material. ##STR6## (where X denotes (.alpha.-OZ, .beta.-H) or (.alpha.-H, .beta.-OZ), with Z representing a protecting group for the hydroxyl group; and R.sup.3 and R.sup.4, which are the same or different, each denote a substituted or unsubstituted alkyl group or phenyl group having 1 to 10 carbon atoms.)
On the other hand, 13-dehydroprostaglandins are known well for their high physiological activity. (J. Fleed et al., J. Med. Chem., 23, 234 (1980)) They are conventionally synthesized by (1) the ring opening reaction of epoxide (J. Fleed et al., Tetrahedron Lett., 3899 (1973)), or (2) the dehydrohalogenation of 14-halogen-substituted-prostaglandins. (Shibasaki et al., J. Org. Chem., 53, 1227 (1988)).